Breaking the Cycle: Can Vitamin D Bridge the Gap Between Gut Microbiota and Immune Dynamics in Multiple Sclerosis?
Abstract
1. Introduction
2. Immune Dysfunction and Microbiota Alterations in Multiple Sclerosis
2.1. Overview of the Innate and Adaptive Immune Systems
2.2. Immune Dysregulation in MS
2.3. Dysbiosis in MS: Key Microbial Alterations and Autoimmunity
2.4. Role of Microbiota-Derived Metabolites in Immune Homeostasis
3. Vitamin D, Gut Microbiota, and Immune Homeostasis: Mechanistic Insights and Clinical Evidence
3.1. The Effect of Vitamin D on Gut Microbiota Composition
3.2. The Impact of Gut Microbiota on Vitamin D Regulation
3.3. Vitamin D, Gut Microbiota, and Immune Homeostasis
3.3.1. Vitamin D/VDR-RXR Complex Stimulates the Transcription of Antimicrobial Peptides
3.3.2. Vitamin D/VDR Signaling Pathway Enhances the Intestinal Mucosal Barrier Integrity
4. Therapeutic Implications and Challenges
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
MS | Multiple Sclerosis |
VDR | Vitamin D receptor |
Th | T Helper Cells |
CNS | Central Nervous System |
RRMS | Relapsing–Remitting Multiple Sclerosis |
PPMS | Primary Progressive Multiple Sclerosis |
SPMS | Secondary Progressive Multiple Sclerosis |
SCFAs | Short-Chain Fatty Acids |
Tregs | T Regulatory Cells |
IL | Interleukin |
TNF-α | Tumor Necrosis Factor Alpha |
AhR | Aryl Hydrocarbon Receptor |
FGF-23 | Fibroblast Growth Factor-23 |
RXR | Retinoid-X Receptor |
AMPs | Antimicrobial Peptides |
ZO | Zonula Occludens |
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Role of Gut Microbiota | Mechanism of Action | References |
---|---|---|
Gut microbiota alterations | Statistically significant differences in both alpha-diversity and beta-diversity Decrease in SCFA-producing bacteria such as Firmicutes, Roseburia, Coprococcus, Lachnospiraceae, Butyricicoccus, Faecalibacterium, Dorea, Lachnospira, and Prevotella Increase certain bacterial genera associated with pro-inflammatory responses, including Bacteroidetes, Akkermansia, and Ruminococcus species | [40] |
Gut-associated immune system | Increased Th1 and Th17 responses due to dysbiosis (microbial antigens, microbial metabolites or dendritic cell mediated effect) Decreased Treg cells due to dysbiosis Autoimmunity due to increased Th1 and Th17 responses Increased levels of pro-inflammatory cytokines Microbial metabolites such as SCFAs alter the expression of immune genes by acting as histone deacetylase inhibitors | [75,79,85,86,89,96] |
Gut–brain axis | Decreased production of SCFAs and impaired intestinal barrier integrity due to dysbiosis (leaky gut) CNS effects and neuro-inflammation due to the passage of exogenous molecules such as bacterial products and metabolites into the bloodstream due to increased intestinal permeability Impaired synthesis of neurotransmitters such as gamma-aminobutyric acid and dopamine due to dysbiosis | [75,93,94,108,109] |
Sample | Mechanism of Action | References |
---|---|---|
Effect of vitamin D supplementation on gut microbiota and intestinal barrier integrity | ||
Male C57BL/6 J mice | Prevention of endotoxemia and maintenance of intestinal barrier function Serum LPS concentration ↓ Caecum ZO-1 and Occludin mRNA relative expression ↑ Improved α-diversity and β-diversity of the gut microbiota Relative abundance of Firmicutes ↓ Relative abundance of Bacteroidetes and Proteobacteria ↑ Gut dysbiosis ↓ | [178] |
Non-obese diabetic mice | Abundance of Lachnospiraceae_FCS020 and Ruminiclostridium_9 ↑ Abundance of Marvinbryantia ↓ | [179] |
C57BL/6J Mice | Colonic ZO-1 and Occludin mRNA relative expression ↑ Relative abundance of Dubosiella newyorkensis ↑ | [180] |
Female C57BL/6J mice | Plasma TMA and TMAO ↓ Increased gut microbial α-diversity indices Relative abundance of Firmicutes ↓ Relative abundance of Bacteroidetes ↑ Bacteroidetes/Firmicutes ratio ↑ Relative abundance of Akkermansia and Ruminiclostridium ↑ | [181] |
Male BALB/C mice | Percentages of Pseudomonas aeruginosa and Salmonella/Shigella spp. ↓ | [182] |
Healthy adults | Bifidobacteriaceae family ↑ | [183] |
Increased gut microbial diversity Relative abundance of Firmicutes ↓ Relative abundance of Bacteroidetes ↑ Bacteroidetes/Firmicutes ratio ↑ Relative abundance of Actinobacteria and Verrucomicrobia ↑ Relative abundance of Bifidobacterium and Akkermansia ↑ Relative abundance of Roseburia, Ruminococcus, and Fecalibacterium ↓ | [128] | |
Relative abundance of Faecalibacterium spp., Clostridia, and Ruminococcaceae ↓ Firmicutes/Bacteroidetes ratio ↓ | [130] | |
No difference was observed in terms of α-diversity. Abundance of genus Lachnospira ↑ Abundance of genus Blautia ↓ Abundance of genus Coprococcus ↑ (>75 nmol/L) Abundance of genus Ruminococcus ↓ (<50 nmol/L) | [184] | |
MS | Majority of operational taxonomic units ↓ Akkermansia, Faecalibacterium, and Coprococcus in untreated MS ↑ | [132] |
Older adults (60–84 y) | No significant difference was observed in gut microbiota composition | [185] |
Infants | Abundance of genus Bilophila, Megamonas and Peptostreptococcus ↓ | [186] |
Relative abundance of Bifidobacterium, Streptococcus, and Lactobacillus ↑ Proportion of Bifidobacterium correlated vitamin D circulating level | [187] | |
Clostridioides Difficile Infected Patients | Abundance of genus Proteobacteria, Enterobacteriaceae and Escherichia ↓ Abundance of Lachnospiraceae, Ruminococcaceae, Christensenellaceae, Bifidobacteriaceae, and Sutterellaceae ↑ | [188] |
Effect of vitamin D supplementation on immune regulation | ||
Male C57BL/6 J mice | TNF-α, IL-1β ↓ | [178] |
Non-obese diabetic mice | Splenic FoxP3+ Treg Cells ↑ IL-10 secretion CD4+ T Cells ↑ Type 1 Diabetes Mellitus incidence ↓ | [179] |
Weaned C57BL/6 mice | Inhibit pro-inflammatory cytokines including IL-1, IL-8, IL-17, and TNF-α | [189] |
25-hydroxyvitamin D-deficient RRMS patients | ↓ IFN-γ secretion by CD4+ T cells received 10,000 IU/week cholecalciferol for 3 months | [156] |
RRMS patients | High-dose group (received 10,000 IU/week cholecalciferol for 6 months) ↓ IL-17 production by CD4+ T cells | [157] |
RRMS patients | Control group (received 50,000 IU cholecalciferol every 5 days for 12 weeks) ↓ IL-17 levels | [158] |
MS patients | Received 50,000 IU cholecalciferol once weekly ↓ TNF-α:IL-5 ratio, ↓ TNF-α:IL-6 ratio, ↓ TNF-α:IL-10 ratio, and ↓ IFN-γ:IL-10 ratio at the 12-month follow-up | [159] |
RRMS patients | Received 20,000 IU/d cholecalciferol for 12 weeks ↑ %IL-17 production by CD4+ T cells | [160] |
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Gençer Bingöl, F.; Kocyigit, E.; Çelik, E.; Ağagündüz, D.; Budán, F. Breaking the Cycle: Can Vitamin D Bridge the Gap Between Gut Microbiota and Immune Dynamics in Multiple Sclerosis? Int. J. Mol. Sci. 2025, 26, 5464. https://doi.org/10.3390/ijms26125464
Gençer Bingöl F, Kocyigit E, Çelik E, Ağagündüz D, Budán F. Breaking the Cycle: Can Vitamin D Bridge the Gap Between Gut Microbiota and Immune Dynamics in Multiple Sclerosis? International Journal of Molecular Sciences. 2025; 26(12):5464. https://doi.org/10.3390/ijms26125464
Chicago/Turabian StyleGençer Bingöl, Feray, Emine Kocyigit, Elif Çelik, Duygu Ağagündüz, and Ferenc Budán. 2025. "Breaking the Cycle: Can Vitamin D Bridge the Gap Between Gut Microbiota and Immune Dynamics in Multiple Sclerosis?" International Journal of Molecular Sciences 26, no. 12: 5464. https://doi.org/10.3390/ijms26125464
APA StyleGençer Bingöl, F., Kocyigit, E., Çelik, E., Ağagündüz, D., & Budán, F. (2025). Breaking the Cycle: Can Vitamin D Bridge the Gap Between Gut Microbiota and Immune Dynamics in Multiple Sclerosis? International Journal of Molecular Sciences, 26(12), 5464. https://doi.org/10.3390/ijms26125464